Upregulation of virulence genes promotes Vibrio cholerae biofilm hyperinfectivity.

Vibrio cholerae remains a major global health threat, disproportionately impacting parts of the world without adequate infrastructure and sanitation resources. In aquatic environments, V. cholerae exists both as planktonic cells and as biofilms, which are held together by an extracellular matrix. V. cholerae biofilms have been shown to be hyperinfective, but the mechanism of hyperinfectivity is unclear. Here we show that biofilm-grown cells, irrespective of the surfaces on which they are formed, are able to markedly outcompete planktonic-grown cells in the infant mouse. Using an imaging technique designed to render intestinal tissue optically transparent and preserve the spatial integrity of infected intestines, we reveal and compare three-dimensional V. cholerae colonization patterns of planktonic-grown and biofilm-grown cells. Quantitative image analyses show that V. cholerae colonizes mainly the medial portion of the small intestine and that both the abundance and localization patterns of biofilm-grown cells differ from that of planktonic-grown cells. In vitro biofilm-grown cells activate expression of the virulence cascade, including the toxin coregulated pilus (TCP), and are able to acquire the cholera toxin-carrying CTXФ phage. Overall, virulence factor gene expression is also higher in vivo when infected with biofilm-grown cells, and modulation of their regulation is sufficient to cause the biofilm hyperinfectivity phenotype. Together, these results indicate that the altered biogeography of biofilm-grown cells and their enhanced production of virulence factors in the intestine underpin the biofilm hyperinfectivity phenotype.

Postmenopausal women's adherence to pelvic floor muscle exercises over 2 years.

OBJECTIVE: This study aimed to investigate women's adherence patterns to pelvic floor muscle exercises (PFME), their associated factors and within-pattern changes. METHODS: This was a secondary analysis using data collected from 647 women aged 55 years and older in the USA. Women were randomly assigned to either a 2-h class group or an equivalent content 20-min DVD group to receive PFME complemented with adherence enhancement strategies. Adherence was assessed at 3, 12 and 24 months using three self-reported items matching PFME parameters. The k-mean clustering and multinomial logistic regression were used to investigate adherence patterns and their associated factors, respectively. Descriptive statistics were used for within-pattern changes over time. RESULTS: Four adherence patterns, A, B, C and D, were identified. Women who displayed optimal adherence to all three aforementioned items, i.e. adherence pattern A, constituted 49.1%, 38.2% and 37.2% of women at 3, 12 and 24 months, respectively. Women with income > US$100,000 were more likely to display adherence pattern A within 12 months. Of women who had adherence pattern A at 3 months, 63.9% and 49.2% continued in this pattern at 12 and 24 months. CONCLUSIONS: Fewer than half of women displayed adherence pattern A for 2 years. Early optimal adherence predicted women's subsequent optimal adherence.

Characteristics Associated With Clinically Important Treatment Responses in Women Undergoing Nonsurgical Therapy for Fecal Incontinence.

OBJECTIVE: To identify baseline clinical and demographic characteristics associated with clinically important treatment responses in a randomized trial of nonsurgical therapies for fecal incontinence (FI). METHODS: Women (N = 296) with FI were randomized to loperamide or placebo- and manometry-assisted biofeedback exercises or educational pamphlet in a 2 × 2 factorial design. Treatment response was defined in 3 ways from baseline to 24 weeks: minimal clinically important difference (MID) of -5 points in St. Mark's score, ≥50% reduction in FI episodes, and combined St. Mark's MID and ≥50% reduction FI episodes. Multivariable logistic regression models included baseline characteristics and treatment groups with and without controlling for drug and exercise adherence. RESULTS: Treatment response defined by St. Mark's MID was associated with higher symptom severity (adjusted odds ratio [aOR] 1.20, 95% confidence interval [CI] 1.11-1.28) and being overweight vs normal/underweight (aOR 2.15, 95% CI 1.07-4.34); these predictors remained controlling for adherence. Fifty percent reduction in FI episodes was associated with the combined loperamide/biofeedback group compared with placebo/pamphlet (aOR 4.04, 95% CI 1.36-11.98), St. Mark's score in the placebo/pamphlet group (aOR 1.29, 95% CI 1.01-1.65), FI subtype of urge vs urge plus passive FI (aOR 2.39, 95% CI 1.09-5.25), and passive vs urge plus passive FI (aOR 3.26, 95% CI 1.48-7.17). Controlling for adherence, associations remained, except St. Mark's score. DISCUSSION: Higher severity of FI symptoms, being overweight, drug adherence, FI subtype, and combined biofeedback and medication treatment were associated with clinically important treatment responses. This information may assist in counseling patients, regarding efficacy and expectations of nonsurgical treatments of FI.

Energy Flux Densities near the Electron Dissipation Region in Asymmetric Magnetopause Reconnection.

Magnetic reconnection is of fundamental importance to plasmas because of its role in releasing and repartitioning stored magnetic energy. Previous results suggest that this energy is predominantly released as ion enthalpy flux along the reconnection outflow. Using Magnetospheric Multiscale data we find the existence of very significant electron energy flux densities in the vicinity of the magnetopause electron dissipation region, orthogonal to the ion energy outflow. These may significantly impact models of electron transport, wave generation, and particle acceleration.

BCG vaccination early in life does not improve COVID-19 outcome of elderly populations, based on nationally reported data.

The reported numbers of Covid-19 cases and deaths were compared for 18 countries (14 in Western Europe, plus Australia, Brazil, Israel and the USA) to assess the effect of historic and current national BCG immunizations. In view of the high death rate for Covid-19 patients over 70 years of age, and given the fact that BCG vaccination is typically given early in life, we compared countries that had introduced BCG in the 1950s with those that had not. No effect on Covid-19 case fatality rate (CFR) or number of deaths per population could be demonstrated. Since some countries test for Covid-19 more than others, the effect of tests performed per million population on reported deaths per million was also assessed, but again did not demonstrate an effect of BCG vaccination in the 1950s. Whether countries had never used the vaccine, had historically used it but since ceased to do so, or were presently vaccinating with BCG did not correlate with national total number of deaths or CFR. We conclude that there is currently no evidence for a beneficial effect of BCG vaccination on Covid-19 reported cases or fatalities.

Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene-level analysis of rare (<1% frequency) single-nucleotide variants (SNVs) revealed that the gene encoding brain-derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.

Are there increased periprocedural complications with the MRI-conditional Medtronic Revo SureScan Pacing System? : A meta-analysis.

BACKGROUND: The use of magnetic resonance imaging (MRI)-conditional permanent pacemakers has increased significantly. In this meta-analysis, we examine the safety of MRI-conditional pacing systems in comparison with conventional systems. METHODS: An electronic search was performed using major databases, including studies that compared the outcomes of interest between patients receiving MRI-conditional pacemakers (MRI group) versus conventional pacemakers (control group). RESULTS: Six studies (5 retrospective and 1 prospective non-randomised) involving 2,118 adult patients were identified. The MRI-conditional pacemakers, deployed in 969 patients, were all from a single manufacturer (Medtronic Pacing System with 5086 leads). The rate of pacemaker lead dislodgement (atrial and ventricular) was significantly higher in the MRI group (3% vs. 1%, OR 2.47 (95% CI 1.26; 4.83), p = 0.008). The MRI group had a significantly higher rate of pericardial complications (2% vs. 1%, OR 4.23 (95% CI 1.18; 15.10), p = 0.03) and a numerically higher overall complication rate in comparison with the conventional group (6% vs. 3%, OR 2.02 (95% CI 0.88; 4.66), p = 0.10) but this was not statistically significant. CONCLUSIONS: In this meta-analysis, the rates of pacemaker lead dislodgement and pericardial complications were significantly higher with the Medtronic MRI-conditional pacing system.

Multipoint Measurements of the Electron Jet of Symmetric Magnetic Reconnection with a Moderate Guide Field.

We report observations from the Magnetospheric Multiscale (MMS) satellites of the electron jet in a symmetric magnetic reconnection event with moderate guide field. All four spacecraft sampled the ion diffusion region and observed the electron exhaust. The observations suggest that the presence of the guide field leads to an asymmetric Hall field, which results in an electron jet skewed towards the separatrix with a nonzero component along the magnetic field. The jet appears in conjunction with a spatially and temporally persistent parallel electric field ranging from -3 to -5 mV/m, which led to dissipation on the order of 8 nW/m^{3}. The parallel electric field heats electrons that drift through it, and is associated with a streaming instability and electron phase space holes.

Separating the wheat from the chaff: systematic identification of functionally relevant noncoding variants in ADHD.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition with negative lifetime outcomes. Uncovering its genetic architecture should yield important insights into the neurobiology of ADHD and assist development of novel treatment strategies. Twenty years of candidate gene investigations and more recently genome-wide association studies have identified an array of potential association signals. In this context, separating the likely true from false associations ('the wheat' from 'the chaff') will be crucial for uncovering the functional biology of ADHD. Here, we defined a set of 2070 DNA variants that showed evidence of association with ADHD (or were in linkage disequilibrium). More than 97% of these variants were noncoding, and were prioritised for further exploration using two tools-genome-wide annotation of variants (GWAVA) and Combined Annotation-Dependent Depletion (CADD)-that were recently developed to rank variants based upon their likely pathogenicity. Capitalising on recent efforts such as the Encyclopaedia of DNA Elements and US National Institutes of Health Roadmap Epigenomics Projects to improve understanding of the noncoding genome, we subsequently identified 65 variants to which we assigned functional annotations, based upon their likely impact on alternative splicing, transcription factor binding and translational regulation. We propose that these 65 variants, which possess not only a high likelihood of pathogenicity but also readily testable functional hypotheses, represent a tractable shortlist for future experimental validation in ADHD. Taken together, this study brings into sharp focus the likely relevance of noncoding variants for the genetic risk associated with ADHD, and more broadly suggests a bioinformatics approach that should be relevant to other psychiatric disorders.

Burden of illness in systemic lupus erythematosus: results from a UK patient and carer online survey.

Objective The objective of this study was to assess the impact of systemic lupus erythematosus (SLE) on patients and carers. Methods Adults with SLE and carers of SLE patients completed a UK-specific online survey covering many aspects of the disease. Surveys were developed in collaboration with an NHS lupus unit and a lupus patient organization. Results A total of 121 patients and 31 carers completed the surveys. Of the 70% of patients initially misdiagnosed with another condition, 59% received treatment for the misdiagnosis. Fatigue was the most debilitating symptom, experienced daily by 79% of patients. The proportion of patients not reporting flares to healthcare providers varied with flare severity: mild flares (43%), moderate flares (15%) and severe flares (5%). Most patients (89%) reported reduced ability to socialize, and 76% had changed employment; of these, 52% stopped working completely. Over one-half (52%) of carers in paid employment missed time from work, and 55% of carers reported a worsened financial status. Most carers (87%) experienced interference with social activities. Conclusion SLE is commonly misdiagnosed and has a considerable impact on the physical, social and financial status of patients and carers. Increased awareness of the disease among healthcare providers and employers of patients and their carers is needed.

Magnetospheric Multiscale Satellites Observations of Parallel Electric Fields Associated with Magnetic Reconnection.

We report observations from the Magnetospheric Multiscale satellites of parallel electric fields (E_{∥}) associated with magnetic reconnection in the subsolar region of the Earth's magnetopause. E_{∥} events near the electron diffusion region have amplitudes on the order of 100 mV/m, which are significantly larger than those predicted for an antiparallel reconnection electric field. This Letter addresses specific types of E_{∥} events, which appear as large-amplitude, near unipolar spikes that are associated with tangled, reconnected magnetic fields. These E_{∥} events are primarily in or near a current layer near the separatrix and are interpreted to be double layers that may be responsible for secondary reconnection in tangled magnetic fields or flux ropes. These results are telling of the three-dimensional nature of magnetopause reconnection and indicate that magnetopause reconnection may be often patchy and/or drive turbulence along the separatrix that results in flux ropes and/or tangled magnetic fields.

A whole blood model of thrombocytopenia that controls platelet count and hematocrit.

In patients with thrombocytopenia, it can be difficult to predict a patient's bleeding risk based on platelet count alone. Platelet reactivity may provide additional information; however, current clinical assays cannot reliably assess platelet function in the setting of thrombocytopenia. New methods to study platelet reactivity in thrombocytopenic samples are needed. In this study, we sought to develop a laboratory model of thrombocytopenia using blood from healthy subjects that preserves the whole blood environment and reproducibly produces samples with a specific platelet count and hematocrit. We compared the activation state of unstimulated and agonist-stimulated platelets in thrombocytopenic samples derived from this method with normocytic controls. Whole blood was diluted with autologous red blood cell concentrate and platelet-poor plasma, which were obtained via centrifugation, in specific ratios to attain a final sample with a predetermined platelet count and hematocrit. P-selectin exposure and GPIIbIIIa activation in unstimulated platelets and platelets stimulated with collagen-related peptide (CRP) or adenosine diphosphate (ADP) in thrombocytopenic samples and the normocytic control from which they were derived were quantified by flow cytometry. Our methodology reliably produced thrombocytopenic samples with a platelet count ≤50,000/µL and an accurately and precisely controlled hematocrit. P-selectin exposure and GPIIbIIIa activation on unstimulated platelets or on ADP- or CRP-stimulated platelets did not differ in thrombocytopenic samples compared to normocytic controls. We describe a new method for creating thrombocytopenic blood that can be used to better understand the contributions of platelet number and function to hemostasis.

Constructing criteria to diagnose the likelihood of extreme events in the case of the electric power grid.

A set of new criteria for the diagnosis of the possible occurrence of a large blackout are constructed, using the output from a model for the dynamics of the electric power grid (the OPA model). The approach used is to look for maximum values of the Transfer Entropy between time series of the system variables and the time series of large blackouts. The best criterion is found by looking at the number of overloaded lines at the beginning of the day.

HIV status and viral loads among men testing positive for rectal gonorrhoea and chlamydia, Maricopa County, Arizona, USA, 2011-2013.

OBJECTIVES: Men diagnosed with rectal gonorrhoea (GC) and chlamydia (CT) have engaged in unprotected receptive anal intercourse. We reviewed the HIV positivity and HIV viral loads (VLs) of men who had rectal GC and CT testing to evaluate potential HIV acquisition and transmission risk. METHODS: Rectal GC and CT testing data for men attending the Maricopa County STD clinic during the period from 1 October 2011 to 30 September 2013 were cross-matched with HIV surveillance data to identify men with HIV coinfection. We examined HIV status, HIV diagnosis date, and the values of VL collected nearest to the date of reported rectal infection. RESULTS: During the 2-year time period, 1591 men were tested for rectal GC and CT. Of the men tested, 506 (31.8%) were positive for GC (13.2%), CT (12.2%) or both (6.4%); 119 (23.5%) of those with rectal GC or CT were coinfected with HIV. Among the 275 men with HIV at the time of rectal testing, 54 (19.6%) had no reported VL; 63 (22.9%) had an undetectable VL (< 20 HIV-1 RNA copies/mL) and 158 (57.4%) had a detectable VL collected within 1 year of rectal diagnosis. Mean VL was higher among HIV and rectal GC/CT coinfected cases compared with men with HIV alone (174 316 vs. 57 717 copies/mL, respectively; P = 0.04). CONCLUSIONS: Approximately one-third of men undergoing rectal testing were positive for GC or CT and one-quarter of men with rectal GC or CT also had HIV infection. Of the HIV-infected men tested for rectal GC or CT, more than half had a detectable VL collected near the time of rectal testing, demonstrating a risk for transmitting HIV.

Women's toileting behaviours: an online survey of female advanced practice providers.

AIMS: An online survey of female advanced practice providers (APPs) in a large urban healthcare system was conducted to describe behaviours they use to manage their personal bladder emptying. METHODS: The questionnaire contained items on demographics, presence of urinary incontinence (UI), and behaviours used to void in work, public and home settings. RESULTS: One hundred thirteen female APPs responded to the survey and 109 responded to items on UI. Over half (53%) reported experiencing UI at least once a week. In general, the APPs reported being worried about the cleanliness of public toilets and delaying voiding when busy. Incontinent APPs were older and had histories of more pregnancies than continent women. Incontinent APPs also used public toilets more frequently and when there was no or little need to void, and delayed or put off voiding while at work and when busy. CONCLUSION: Although APPs have specialised knowledge about lower urinary tract anatomy and physiology, many engage in behaviours that may be detrimental to bladder health. More research is needed to explore behaviours women use to manage voiding and the effect of these behaviours on bladder health.

Cerenkov emission of quasiparallel whistlers by fast electron phase-space holes during magnetic reconnection.

Kinetic simulations of magnetotail reconnection have revealed electromagnetic whistlers originating near the exhaust boundary and propagating into the inflow region. The whistler production mechanism is not a linear instability, but rather is Cerenkov emission of almost parallel whistlers from localized moving clumps of charge (finite-size quasiparticles) associated with nonlinear coherent electron phase space holes. Whistlers are strongly excited by holes without ever growing exponentially. In the simulation the whistlers are emitted in the source region from holes that accelerate down the magnetic separatrix towards the x line. The phase velocity of the whistlers vφ in the source region is everywhere well matched to the hole velocity vH as required by the Cerenkov condition. The simulation shows emission is most efficient near the theoretical maximum vφ=half the electron Alfven speed, consistent with the new theoretical prediction that faster holes radiate more efficiently. While transferring energy to whistlers the holes lose coherence and dissipate over a few local ion inertial lengths. The whistlers, however, propagate to the x line and out over many 10's of ion inertial lengths into the inflow region of reconnection. As the whistlers pass near the x line they modulate the rate at which magnetic field lines reconnect.

Are we shortchanging frail older people when it comes to the pharmacological treatment of urgency urinary incontinence?

Overactive bladder and urgency incontinence are common and distressing conditions in older people, for which the first-line pharmacological treatment is a bladder antimuscarinic agent. Of these, oxybutynin is often recommended in guidelines, but is associated with a higher incidence of adverse drug effects, and in particular has been suggested to have deleterious cognitive effects. Despite this, guidelines often suggest oxybutynin as first-line treatment, and insurance based healthcare systems often require oxybutynin to be used as a first-line therapy and fail before reimbursement for the cost of newer anticholinergics is authorised. We reviewed the literature of bladder antimuscarinics in older adults, using the headings overactive bladder, urinary frequency, urgency, urge, oxybutynin, antimuscarinic, older, older people, and frail. In general, oxybutynin had a similar efficacy to other anticholinergic drugs, but a higher incidence of adverse drug events, in particular significant yet unnoticed cognitive impairment. We conclude that oxybutynin should not be used in frail older people.

Does size matter?

Failures of the complex infrastructures society depends on having enormous human and economic cost that poses the question: Are there ways to optimize these systems to reduce the risks of failure? A dynamic model of one such system, the power transmission grid, is used to investigate the risk from failure as a function of the system size. It is found that there appears to be optimal sizes for such networks where the risk of failure is balanced by the benefit given by the size.

Obstruction in Hypertrophic Cardiomyopathy: Many Faces.

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy, exhibits left ventricular hypertrophy not secondary to other causes, with varied phenotypic expression. Enhanced actin-myosin interaction underlies excessive myocardial contraction, frequently resulting in dynamic obstruction within the left ventricle. Left ventricular outflow tract obstruction, occurring at rest or with provocation in 75% of HCM patients, portends adverse prognosis, contributes to symptoms, and is frequently a therapeutic target. Transthoracic echocardiography plays a crucial role in the screening, initial diagnosis, management, and risk stratification of HCM. Herein, we explore echocardiographic evaluation of HCM, emphasizing Doppler assessment for obstruction. Echocardiography informs management strategies through noninvasive hemodynamic assessment, which is frequently obtained with various provocative maneuvers. Recognition of obstructive HCM phenotypes and associated anatomical abnormalities guides therapeutic decision-making. Doppler echocardiography allows monitoring of therapeutic responses, whether it be medical therapies (including cardiac myosin inhibitor therapy) or septal reduction therapies, including surgical myectomy and alcohol septal ablation. This article discusses the hemodynamics of obstruction and practical application of Doppler assessment in HCM. In addition, it provides a visual atlas of obstruction in HCM, including high-quality figures and complementary videos that illustrate the many facets of dynamic obstruction.